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Objective: To determine whether serum urate reduction with allopurinol lowers blood pressure (BP) in young adults and the mechanisms mediating this hypothesized effect., Methods: We conducted a single-center, randomized, double-blind, crossover clinical trial. Adults ages 18-40 years with baseline systolic BP ≥120 and <160 mm Hg or diastolic BP ≥80 and <100 mm Hg, and serum urate ≥5.0 mg/dl for men or ≥4.0 mg/dl for women were enrolled. Main exclusion criteria included chronic kidney disease, gout, or past use of urate-lowering therapies. Participants received oral allopurinol (300 mg daily) or placebo for 1 month followed by a 2-4 week washout and then were crossed over. Study outcome measures were change in systolic BP from baseline, endothelial function estimated as flow-mediated dilation (FMD), and high-sensitivity C-reactive protein (hsCRP) levels. Adverse events were assessed., Results: Ninety-nine participants were randomized, and 82 completed all visits. The mean ± SD age was 28.0 ± 7.0 years, 62.6% were men, and 40.4% were African American. In the primary intent-to-treat analysis, systolic BP did not change during the allopurinol treatment phase (mean ± SEM -1.39 ± 1.16 mm Hg) or placebo treatment phase (-1.06 ± 1.08 mm Hg). FMD increased during allopurinol treatment periods compared to placebo treatment periods (mean ± SEM 2.5 ± 0.55% versus -0.1 ± 0.42%; P < 0.001). There were no changes in hsCRP level and no serious adverse events., Conclusion: Our findings indicate that urate-lowering therapy with allopurinol does not lower systolic BP or hsCRP level in young adults when compared with placebo, despite improvements in FMD. These findings do not support urate lowering as a treatment for hypertension in young adults., (© 2021, American College of Rheumatology.)

Importance: Higher blood pressure (BP) levels in children are associated with an increased risk for hypertension and subclinical cardiovascular disease in adulthood. Identifying trends in BP could inform the need for interventions to lower BP., Objective: To determine whether systolic BP (SBP) and diastolic BP (DBP) levels among US children have changed during the past 20 years., Design, Setting, and Participants: This serial cross-sectional analysis of National Health and Nutrition Examination Survey data included 9117 children aged 8 to 12 years and 10 156 adolescents aged 13 to 17 years, weighted to the US population from 1999-2002 to 2015-2018. Data were collected from March 1999 to December 2018 and analyzed from March 26, 2020, to February 2, 2021., Exposures: Calendar year., Main Outcomes and Measures: The primary outcomes were mean SBP and mean DBP., Results: A total of 19 273 participants were included in the analysis. Among children aged 8 to 12 years in 2015-2018 (mean age, 10.5 [95% CI, 10.5-10.6] years), 48.7% (95% CI, 45.2%-52.2%) were girls and 51.3% (95% CI, 47.8%-54.8%) were boys; 49.7% (95% CI, 42.2%-57.1%) were non-Hispanic White; 13.7% (95% CI, 10.3%-18.1%) were non-Hispanic Black; 25.5% (95% CI, 19.9%-32.0%) were Hispanic; 4.7% (95% CI, 3.2%-6.7%) were non-Hispanic Asian; and 6.5% (95% CI, 4.9%-8.5%) were other non-Hispanic race/ethnicity. Among those aged 13 to 17 years in 2015-2018 (mean age, 15.5 [95% CI, 15.5-15.5] years), 49.1% (95% CI, 46.1%-52.2%) were girls and 50.9% (95% CI, 47.8%-53.9%) were boys; 53.3% (95% CI, 46.4%-60.1%) were non-Hispanic White; 13.9% (95% CI, 10.3%-18.7%) were non-Hispanic Black; 21.9% (95% CI, 16.6%-28.2%) were Hispanic; 4.6% (95% CI, 3.2%-6.5%) were non-Hispanic Asian; and 6.3% (95% CI, 4.7%-8.5%) were other non-Hispanic race/ethnicity. Among children aged 8 to 12 years, age-adjusted mean SBP decreased from 102.4 (95% CI, 101.7-103.1) mm Hg in 1999-2002 to 101.5 (95% CI, 100.8-102.2) mm Hg in 2011-2014 and then increased to 102.5 (95% CI, 101.9-103.2) mm Hg in 2015-2018. Age-adjusted mean DBP decreased from 57.2 (95% CI, 56.5-58.0) mm Hg in 1999-2002 to 51.9 (95% CI, 50.1-53.7) mm Hg in 2011-2014 and increased to 53.2 (95% CI, 52.2-54.1) mm Hg in 2015-2018. Among adolescents aged 13 to 17 years, age-adjusted mean SBP decreased from 109.2 (95% CI, 108.7-109.7) mm Hg in 1999-2002 to 108.4 (95% CI, 107.8-109.1) mm Hg in 2011-2014 and remained unchanged in 2015-2018 (108.4 [95% CI, 107.8-109.1] mm Hg). Mean DBP decreased from 62.6 (95% CI, 61.7-63.5) mm Hg in 1999-2002 to 59.6 (95% CI, 58.2-60.9) mm Hg in 2011-2014 and then increased to 60.8 (95% CI, 59.8-61.7) mm Hg in 2015-2018. Among children aged 8 to 12 years, mean SBP was 3.2 (95% CI, 1.7-4.6) mm Hg higher among those with overweight and 6.8 (95% CI, 5.6-8.1) mm Hg higher among those with obesity compared with normal weight; mean DBP was 3.2 (95% CI, 0.7-5.6) mm Hg higher among those with overweight and 3.5 (95% CI, 1.9- 5.1) mm Hg higher among those with obesity compared with normal weight. Among adolescents aged 13 to 17 years, mean SBP was 3.5 (95% CI 1.9-5.1) mm Hg higher among those with overweight and 6.6 (95% CI, 5.2-8.0) mm Hg higher among those with obesity compared with normal weight, 4.8 (95% CI, 3.8-5.8) mm Hg higher among boys compared with girls, and 3.0 (95% CI, 1.7-4.3) mm Hg higher among non-Hispanic Black compared with non-Hispanic White participants., Conclusions and Relevance: Despite an overall decline in mean SBP and DBP from 1999-2002 to 2015-2018, BP levels among children and adolescents may have increased from 2011-2014 to 2015-2018.

Background: Hyperuricemia is associated with hypertension, with elevated serum uric acid levels postulated to have a causal role in the development of hypertension. Consequently, serum uric acid reduction may help lower blood pressure (BP). A Phase 2, double-blind, placebo-controlled trial was conducted to assess the potential BP-lowering effects of the xanthine oxidase inhibitor febuxostat in subjects with hypertension and hyperuricemia (serum uric acid ≥0.42 mmol/L [≥7.0 mg/dL])., Methods and Results: Subjects (n=121) were randomized 1:1 to febuxostat 80 mg once daily or to placebo. The primary end point was change from baseline to Week 6 in 24-hour mean ambulatory systolic BP (SBP). Additional end points included the following: change from baseline to Week 3 in 24-hour mean SBP and changes from baseline to Weeks 3 and 6 in 24-hour mean ambulatory diastolic BP, serum uric acid, mean daytime and nighttime ambulatory SBP/diastolic BP, and clinic SBP/diastolic BP. For the overall study population, there were no significant differences between febuxostat and placebo for changes from baseline to Weeks 3 or 6 in ambulatory, daytime or nighttime, or clinic SBP or diastolic BP. However, in a preplanned subgroup analysis, there was a significant decrease in SBP from baseline to Week 6 in subjects with normal renal function (estimated glomerular filtration rate ≥90 mL/min) treated with febuxostat versus placebo; least squares mean difference, -6.7; 95% confidence interval -13.3 to -0.0; P =0.049., Conclusions: This study suggests that febuxostat may lower BP in hyperuricemic patients with hypertension and normal renal function; further studies should be conducted to confirm this finding., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01496469., (© 2017 The Authors and Takeda Pharmaceuticals. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Patients with sickle cell anemia (SCA) have an increased prevalence of nephropathy and mortality from chronic kidney disease (CKD)., Methods: We evaluated the association of hyperuricemia and nocturnal hypertension with lower estimated glomerular filtration rate (eGFR) using cystatin-C in patients aged 10-21 years with the HbSS or HbSB0 form of the disease during a non-acute clinic visit. eGFR and uric acid measurements were obtained in 83 and 81 participants, respectively, and 24-h ambulatory blood pressure monitoring (ABPM) was performed in 44 participants. Annual testing included vital signs, complete blood count, comprehensive metabolic panel, medications, urine microalbumin/creatinine, and lactate dehydrogenase measurements. Hyperuricemia was defined as a uric acid level of ≥5.5 mg/dL. Nocturnal hypertension was defined as >25% of nocturnal readings at >95th percentile according to norms established by the American Heart Association Statement on ABPM in children and adolescents., Results: The mean eGFR was statistically significantly lower in patients with hyperuricemia than in those with normal uric acid levels (143 vs. 161 mL/min/1.73 m 2 , respectively). Of the 44 participants for whom ABPM data were available, 14 (32%) had systolic nocturnal hypertension and 12 (27%) had diastolic nocturnal hypertension. The mean eGFR was statistically significantly lower in participants with nocturnal systolic and diastolic hypertension than in those with normal nocturnal blood pressure. In a regression model, nocturnal hypertension and hyperuricemia were associated with a lower eGFR., Conclusions: Two risk factors for CKD, i.e., nocturnal hypertension and hyperuricemia, were associated with lower eGFR in older children and adolescent patients with SCA. Long-term studies on their association with progression to CKD in this population are warranted., Key Point: Nocturnal hypertension and hyperuricemia are established risk factors for nephropathy in other diseases and may play a role in SCA nephropathy.

Purpose of Review: To discuss the evolving data regarding uric acid as a potential cause of hypertension and progressive renal dysfunction and its clinical and research implications., Recent Findings: The potential mechanisms by which uric acid could cause vasoconstriction and a progressive ateriolopathy were established in animal models between 1999 and 2004. Since then, there has been a growing interest in the topic and numerous retrospective and prospective observational studies. The preponderance of data support the hypothesis that serum uric acid is a cause or exacerbating factor of hypertension and progressive kidney disease. Over the last couple of years clinical intervention trials, including randomized controlled trials in the young have supported this mechanistic role., Summary: Current evidence supports the role of uric acid as marker and mediator of risk for both hypertension and progressive decline in renal function. Data on the impact of xanthine oxidase inhibitors or uricosurics on clinical hypertension and chronic kidney disease are suggestive but inconclusive. Considerably, more data will be required to determine if uric acid lowering therapy will become a mainstay of management in diseases other than gout and tumor lysis syndrome.

Purpose of Review: Studies have shown an association between hyperuricemia and essential hypertension in children, presenting the possibility for serum uric acid level to serve as a biomarker for diagnosis and potential treatment target., Recent Findings: The proposed mechanism of uric acid-induced hypertension is biphasic, with a reversible early phase, implying added significance for new-onset hypertension. Current evidence shows a strong correlation between uric acid level and essential hypertension, supporting its use in diagnosis. Small studies have shown that the use of uric acid-lowering agents allopurinol and probenecid can lower blood pressure in adolescents. These medications require further study in large populations and careful consideration of their side-effect profiles prior to clinical use as antihypertensive agents. Recent studies have also linked dietary fructose intake to hyperuricemia and hypertension, but the clinical effect of fructose reduction on blood pressure has not been confirmed., Summary: Current evidence supports use of serum uric acid level as a biomarker for diagnosis of essential hypertension in children. More research is needed to evaluate the utility of pharmacologic and nonpharmacologic means of serum uric acid reduction prior to clinical use as a therapy for hypertension.

Over the past century, uric acid has been considered a possible risk factor for hypertension and cardiovascular disease. However, only in the past decade, animal models and clinical trials have supported a more mechanistic link. Results from animal models suggest a 2-phase mechanism for the development of hyperuricemic hypertension in which uric acid induces acute vasoconstriction by activation of renin-angiotensin system, followed by uric acid uptake into vascular smooth muscle cells leading to cellular proliferation and secondary arteriolosclerosis that impairs pressure natriuresis. This acute hypertension remains uric acid dependent and sodium independent, whereas the chronic hypertension becomes uric acid independent and sodium dependent. Small clinical trials, performed in adolescents with newly diagnosed essential hypertension, demonstrate that reduction of serum uric acid can reduce blood pressure. Although more research is clearly necessary, the available data suggest that uric acid is likely causative in some cases of early onset hypertension., (Copyright © 2012 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Uric acid has been suspected to be a risk factor for hypertension since the 1870s. Numerous epidemiological studies demonstrate an association between uric acid and both incident and prevalent hypertension in diverse populations. Studies in elderly patients have had more variable results, raising the possibility that uric acid may be more significant to hypertension in the young. Animal models support a two-phase mechanism for the development of hyperuricemic hypertension. Initially, uric acid induces vasoconstriction by activation of the renin-angiotensin system and reduction of circulating nitric oxide, which can be reversed by lowering uric acid. Over time, uric acid uptake into vascular smooth muscle cells causes cellular proliferation and secondary arteriolosclerosis that impairs pressure natriuresis, causing sodium-sensitive hypertension. Consistent with the animal model data, small clinical trials performed in adolescents with newly diagnosed essential hypertension demonstrate that at least in certain young patients, reduction of serum uric acid can mitigate blood pressure elevation. While more research is clearly necessary, the available data suggest that uric acid is likely causative in some cases of early-onset hypertension., (© 2012 Wiley Periodicals, Inc.)

A link between serum uric acid and the development of hypertension was first hypothesized in the 1870s. Although numerous epidemiologic studies in the 1980s and 1990s suggested an association, relatively little attention was paid to it until recently. Animal models have suggested a two-step pathogenesis by which uric acid initially activates the renin angiotensin system and suppresses nitric oxide, leading to uric acid-dependent increase in systemic vascular resistance, followed by a uric acid-mediated vasculopathy, involving renal afferent arterioles, resulting in a late sodium-sensitive hypertension. Initial clinical trials in young patients have supported these mechanisms in young patients but do not yet support pharmacologic reduction of serum uric acid as first-line therapy for hypertension., (Copyright © 2011. Published by Elsevier Inc.)

Serum uric acid (UA) is positively associated with hypertension (HTN). HTN is common in pediatric patients receiving hemodialysis (HD) and peritoneal dialysis (PD). We assessed the relationship between UA and BP in 63 pediatric dialysis patients by measuring pre-treatment UA levels and BP in HD patients and in-center UA levels and blood pressure (BP) in PD patients. UA levels were similar in both groups [6.8 ± 0.2 (HD) vs. 6.5 ± 0.3 (PD), p = 0.6]. Pre-treatment systolic BP percentile was associated with a high UA level [91.9 ± 2.3 (>6.0 mg/dL) vs. 79.3 ± 5.8 mm Hg (≤6.0 mg/dL), p = 0.01] in HD patients only. There was a negative relationship between UA and dialysis vintage (r = -0.31, p = 0.01). In both groups, there was no relationship between UA and Kt/V. In HD patients, fluid overload was unrelated to UA level [4.2 ± 0.6% (≤6.0 mg/dL) vs. 4.3 ± 0.3% (>6.0 mg/dL), p = 0.9]. Moreover, pre-HD treatment systolic BP percentile correlated with UA (beta 0.36, p = 0.02) independent of volume. UA levels were higher in patients receiving anti-hypertensive medications [6.3 ± 0.2 (No Meds] vs 7.0 ± 0.2 (BP Meds) mg/dL,  p= 0.01]. Finally, there was no relationship between serum UA and normalized protein catabolic rate (r = 0.14; p = 0.4). In summary, serum UA impacts BP in pediatric HD patients, independent of volume, nutritional and weight status.

Objective: To determine the efficacy and safety of labetalol for hypertensive crisis in children ≤ 24 months of age., Design: Retrospective chart review. Statistical analysis utilized analysis of variance for continuous data, chi-square tests for nominal data, and linear regression., Setting: A 737-bed pediatric teaching institution., Patients: Twenty-seven patients ≤ 24 months of age were treated with 37 intravenous infusions of labetalol, nicardipine, or nitroprusside for hypertensive crisis or hypertensive urgency., Interventions: None., Measurements and Main Results: The primary end point consisted of time to 20% reduction in systolic blood pressure. Primary safety end points measured the prevalence of deleterious effects of labetalol. Continuous infusion of labetalol reduced mean systolic blood pressure by at least 20% in < 8 hrs. This effect was similar to nicardipine and nitroprusside infusions. The reported side effects were similar in each group. Patients receiving labetalol and presenting with ischemic or traumatic brain injury were likely to develop hypotension requiring infusion discontinuation., Conclusions: Continuous intravenous labetalol infusion is efficacious for treatment of hypertensive crisis in children ≤ 24 months of age. Aside from patients presenting with ischemic or traumatic brain injury, labetalol was safe to use in this population for hypertensive emergencies and had a satisfactory adverse effect profile. Labetalol may reach dose saturation at a much lower dose in young children in comparison to adults. Clinicians should use caution when initiating labetalol infusions in young patients with brain injury.

Consumption of sugar-sweetened beverages has been associated with the development and maintenance of obesity, as well as the risk for multiple obesity-related comorbidities. Some experts have hypothesized that the effect is entirely associated with excess caloric intake, while others suggest that a component of sweeteners may have a physiologic impact on the development of hypertension, insulin resistance and nonalcoholic fatty liver disease. Chen et al. have presented the first, large-scale clinical trial, assessing the direct effect of modest changes in sweetened drink consumption on blood pressure in a racially diverse population. The study team utilized data from the PREMIER: Lifestyle Interventions for Blood Pressure Control trial, in which 810 adult subjects were randomized to three groups: advice only; comprehensive lifestyle modification aimed at weight loss, increased exercise and dietary sodium reduction; or comprehensive lifestyle modification with incorporation of the Dietary Approach to Stop Hypertension (DASH) diet. Sweetened drink intake was estimated from 24-h subject recall, assessed by unscheduled phone calls to subjects at baseline, 6 months and 18 months. Over the duration of the study, a reduction of one 12-oz serving of sugar-sweetened beverages per day was associated with an average of 1.8 mmHg reduction in systolic blood pressure and an average of 1.1 mmHg reduction in diastolic blood pressure.

Uric acid was first associated with primary hypertension in 1874, yet its role in this condition remains unclear. Historically, uric acid was thought to be a secondary response to hypertension or its associated conditions. However, more recent experimental and clinical studies suggest that uric acid could have a contributory role in the pathogenesis of elevated blood pressure. More studies are needed to help dissect the potential mechanisms by which uric acid could initiate this response. It remains possible that uric acid is a marker for xanthine oxidase-associated oxidants and that the latter could be driving the hypertensive response. However, the weight of the evidence suggests that uric acid is a true modifying and possibly causal factor for human primary hypertension. Hence, early management of hyperuricemia might delay the development of essential hypertension.

Objective: The goal was to determine the cost-effectiveness of ambulatory blood pressure monitoring in the initial evaluation of stage 1 hypertension., Methods: Retrospective chart review of data for children referred to Texas Children's Hospital hypertension clinic between January 2005 and August 2006 was performed. We compared the costs of standard evaluations versus the initial use of ambulatory blood pressure monitoring for children with clinic blood pressure measurements suggesting stage 1 hypertension. Charges for clinic visits, laboratory tests, and imaging were obtained from the Texas Children's Hospital billing department., Results: A total of 267 children were referred. One hundred thirty-nine children did not receive ambulatory blood pressure monitoring; 54 met clinical indications for ambulatory blood pressure monitoring but did not receive it because it was not a covered expense (44 children) or the family refused the study (10 children). One hundred twenty-six children received clinically indicated ambulatory blood pressure monitoring, paid for either through insurance or by the family. Fifty-eight children (46%) had confirmed white-coat hypertension, 62 (49%) stage 1 hypertension, and 6 (5%) stage 2 hypertension. With the observed prevalence of white-coat hypertension, initial ambulatory blood pressure monitoring use yielded net savings after evaluation of 3 patients, with projected savings of $2.4 million per 1000 patients., Conclusions: Ambulatory blood pressure monitoring in the initial evaluation of suspected childhood hypertension is highly cost-effective. Awareness of cost saving potential may increase the availability of ambulatory blood pressure monitoring for evaluation of new-onset hypertension.

Context: Hyperuricemia is a predictor for the development of hypertension and is commonly present in new-onset essential hypertension. Experimentally increasing uric acid levels using a uricase inhibitor causes systemic hypertension in animal models., Objective: To determine whether lowering uric acid lowers blood pressure (BP) in hyperuricemic adolescents with newly diagnosed hypertension., Design, Setting, and Patients: Randomized, double-blind, placebo-controlled, crossover trial (September 2004-March 2007) involving 30 adolescents (aged 11-17 years) who had newly diagnosed, never-treated stage 1 essential hypertension and serum uric acid levels > or = 6 mg/dL. Participants were treated at the Pediatric Hypertension Clinic at Texas Children's Hospital in Houston. Patients were excluded if they had stage 2 hypertension or known renal, cardiovascular, gastrointestinal tract, hepatic, or endocrine disease., Intervention: Allopurinol, 200 mg twice daily for 4 weeks, and placebo, twice daily for 4 weeks, with a 2-week washout period between treatments. The order of the treatments was randomized., Main Outcome Measures: Change in casual and ambulatory blood pressure., Results: For casual BP, the mean change in systolic BP for allopurinol was -6.9 mm Hg (95% confidence interval [CI], -4.5 to -9.3 mm Hg) vs -2.0 mm Hg (95% CI, 0.3 to -4.3 mm Hg; P = .009) for placebo, and the mean change in diastolic BP for allopurinol was -5.1 mm Hg (95% CI, -2.5 to -7.8 mm Hg) vs -2.4 (95% CI, 0.2 to -4.1; P = .05) for placebo. Mean change in mean 24-hour ambulatory systolic BP for allopurinol was -6.3 mm Hg (95% CI, -3.8 to -8.9 mm Hg) vs 0.8 mm Hg (95% CI, 3.4 to -2.9 mm Hg; P = .001) for placebo and mean 24-hour ambulatory diastolic BP for allopurinol was -4.6 mm Hg (-2.4 to -6.8 mm Hg) vs -0.3 mm Hg (95% CI, 2.3 to -2.1 mm Hg; P = .004) for placebo. Twenty of the 30 participants achieved normal BP by casual and ambulatory criteria while taking allopurinol vs 1 participant while taking placebo (P < .001)., Conclusions: In this short-term, crossover study of adolescents with newly diagnosed hypertension, treatment with allopurinol resulted in reduction of BP. The results represent a new potential therapeutic approach, although not a fully developed therapeutic strategy due to potential adverse effects. These preliminary findings require confirmation in larger clinical trials., Trial Registration: clinicaltrials.gov Identifier: NCT00288184.

Objective: Hypertension is common in the pediatric population. There is increasing evidence for early hypertensive target organ damage that may lead to substantial long-term morbidity. Because a critical aspect of any screening program for hypertension is the ability to measure blood pressure accurately, we compared typical blood pressure measurements at a vital sign station with those that were obtained following recommendations set forth in "The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents.", Methods: We compared the blood pressure measurements that were obtained with standard practice vital sign station screening with those that were obtained by trained personnel in accordance with Fourth Task Force recommendations. A total of 390 children were evaluated at 580 visits to the Pediatric Hypertension Clinic at Texas Children's Hospital., Results: Seventy-four percent of the readings were higher at the vital sign station, and only 12% differed by <5 mm Hg for both systolic blood pressure and diastolic blood pressure. The mean difference between vital sign station and examination room was 13.2 +/- 8.9 mm Hg for systolic blood pressure and 9.6 +/- 7.6 mm Hg for diastolic blood pressure. Multiple regression analyses revealed that age, gender, race, obesity, first versus subsequent visit, essential versus secondary, or white coat hypertension and antihypertensive medications made no statistically significant difference in the lack of correlation of the readings., Conclusion: These results suggest that if pediatricians use vital sign station screening for blood pressure, children with elevated initial measurements must be reevaluated in the examination room.

Over the past few years, increasing evidence has supported the possible role of uric acid as a mediator of high blood pressure. Both animal model data and tissue culture experiments suggest that uric acid might cause increased blood pressure through a 2-phase process. The first phase is dominated by a uric acid-mediated vasoconstriction followed by induction of renal afferent arteriolosclerosis and altered pressure natriuresis, leading to sodium-dependent hypertension. We have assessed children with newly diagnosed essential hypertension through cross-sectional studies and clinical trials. Elevated uric acid is closely associated with new-onset essential hypertension in children, and preliminary data suggest that lowering of uric acid can lower blood pressure in some patients. Future studies will be needed to determine whether the mechanisms shown in animal models can be extrapolated to children.

Epidemiologic studies published during the past 3 years support the possible role of uric acid in the onset of essential hypertension. Data from several large, longitudinal cardiovascular disease studies indicate that elevated serum uric acid is a predictor of incident hypertension and blood pressure progression. In a pediatric study, more than 90% of children with essential hypertension have serum uric acid levels above 5.5 mg/dL. During the same period, laboratory studies have provided compelling mechanistic evidence to explain the clinical observations. Uric acid causes hypertension in a rat model through the activation of the renin-angiotensin system, downregulation of nitric oxide, and induction of endothelial dysfunction and vascular smooth muscle proliferation. Ongoing clinical trials will elucidate the role of uric acid in human hypertension and will determine whether control of uric acid may be a new way to prevent or treat essential hypertension.

Serum uric acid was first noted to be associated with increased BP by Frederick Mohamed in the 1870s. Although the link was rediscovered periodically over the years, it generally was dismissed as a surrogate marker for decreased renal function that led to increased uric acid and increased risk for hypertension and cardiovascular (CV) disease. Recently, however, several lines of evidence suggest that increased serum uric acid may be a significant modifiable risk factor. Increased serum uric acid is associated with increased risk for future hypertension in several large longitudinal clinical trials as well as an independent risk factor for poor CV prognosis. Animal model experiments demonstrate that increased serum uric acid causes increased BP that initially is reversible but becomes irreversible, salt sensitive, and uric acid independent over time. The mechanisms include the direct action of uric acid on smooth muscle and vascular endothelial cells. Finally, in adolescents with new-onset essential hypertension, the prevalence of elevated serum uric acid is >90%, and preliminary clinical trial evidence suggests that agents that lower serum uric acid may lower BP in this select population. Although the investigations are still preliminary, serum uric acid represents a possible new and intriguing target for the reduction of morbidity and mortality associated with hypertension and CV disease.

Early hypertension has generally been considered to be an asymptomatic condition; however, recent data show that many hypertensive children have evidence of end organ damage. We sought to determine if a spectrum of common symptoms is associated with early hypertension and whether those symptoms resolve with lowered blood pressure. Four hundred and nine consecutive children, 7-18 years old, examined in the Texas Children's Hospital Hypertension Clinic for new-onset high blood pressure (BP) completed a questionnaire, including the self-reporting of 15 symptoms potentially attributed to high blood pressure. Subjects received anti-hypertensive treatment and repeated the questionnaire 4-6 months after initiation of therapy. One-hundred fifty healthy, normotensive children completed the questionnaire as controls. Of hypertensive children, 64% were symptomatic, compared with 26% of normotensive children (P<0.001). Fifty-one percent of hypertensive children reported 1-4 symptoms, 14% >4 symptoms. Following treatment only 28% of children remained symptomatic. The three most common symptoms in hypertensive patients, headache, 42%, difficulty initiating sleep, 27%, and daytime tiredness, 26%, were markedly reduced with treatment, to 6.2%, 1.5% and 10%, respectively (P<0.001). We conclude that newly diagnosed hypertensive children had a variety of non-specific symptoms, more prevalent than those of normotensive children, and most somatic complaints improved with 4-6 months of anti-hypertensive treatment.

Hypertension is the most common form of cardiovascular disease. Although it is less common in adolescents than in adults, hypertension and the associated organ damage can and often does begin early in life. Consequently, for many with high blood pressure (BP), measures directed at the long-term prevention of cardiovascular morbidity may need to be started in adolescence to achieve maximal effectiveness. This article discusses some of the problems unique to hypertension in the young, as well as recent discoveries regarding the likely role played by increases in serum uric acid level in the development of adolescent-onset essential hypertension.

Background: Essential hypertension affects more than 25% of the world's population. Genetic, physiologic, and epidemiologic studies provide clues to its origins, but a clear understanding has been elusive. Recent experimental and clinical studies have implicated uric acid in the onset of essential hypertension., Methods: In a retrospective chart review, we identified 95 children with confirmed, new onset hypertension, and evaluated the cause of hypertension and parental history of hypertension, birth weight, and serum uric acid. In an open-label, cross-over trial we treated 5 children with confirmed essential hypertension with allopurinol as single treatment agent, and screened for change in blood pressure by casual and ambulatory methods. In tissue culture experiments, we evaluated the effect of uric acid on glomerular endothelial cell function., Results: Elevation of serum uric acid is related to the onset of essential hypertension in children, reduced birth weight, and endothelial dysfunction. Normalization of uric acid appears to ameliorate new onset essential hypertension., Conclusion: These findings, combined with animal model data, support the hypothesis that uric acid has a key role in the pathogenesis of early onset essential hypertension, and may unify some of the disparate theories of the origins of essential hypertension.

Experimental animal models suggest that uric acid might have a pathogenic role in the early development of primary hypertension. We hypothesized that serum uric acid is correlated with blood pressure in children with new-onset, untreated, primary hypertension. We evaluated 125 consecutive children referred to the Baylor Pediatric Renal Program for evaluation of hypertension. None of the subjects had previously been evaluated or treated for hypertension. The children ranged in age from 6 to 18 years (mean, 13.4+/-3.3) and had normal renal function (creatinine clearance >80 mL x min(-1) x 1.73 m(-2)). Sixty-three children had primary hypertension, 40 had secondary hypertension, and 22 had white-coat hypertension. Forty controls with normal blood pressure were recruited from the renal clinic. Uric acid levels were directly correlated with systolic (r=0.80, P=0.0002) and diastolic (r=0.66, P=0.0006) blood pressure in controls and in subjects with primary hypertension and were independent of renal function. Serum uric acid concentrations >5.5 mg/dL were found in 89% of subjects with primary hypertension, in 30% with secondary hypertension, in 0% with white-coat hypertension, and in 0% of controls. We conclude that serum uric acid is directly correlated with blood pressure in untreated children and that a serum uric acid value >5.5 mg/dL in an adolescent being evaluated for hypertension strongly suggests primary hypertension as opposed to white-coat or secondary hypertension. These results are consistent with the hypothesis that uric acid might have a role in the early pathogenesis of primary hypertension.

Despite its discovery more than 150 years ago, the cause of primary hypertension remains unknown. Most studies suggest that hypertension involves genetic, congenital or acquired risk factors that result in a relative inability of the kidney to excrete salt (sodium chloride) in the kidneys. Here we review recent studies that suggest there may be two phases, with an initial phase driven by renal vasoconstriction that causes low-grade ischemia to the kidney, followed by the infiltration of immune cells that leads to a local autoimmune reaction that maintains the renal vasoconstriction. Evidence suggests that multiple mechanisms could trigger the initial renal vasoconstriction, but one way may involve fructose that is provided in the diet (such as from table sugar or high fructose corn syrup) or produced endogenously. The fructose metabolism increases intracellular uric acid, which recruits NADPH oxidase to the mitochondria while inhibiting AMP-activated protein kinase. A drop in intracellular ATP level occurs, triggering a survival response. Leptin levels rise, triggering activation of the sympathetic central nervous system, while vasopressin levels rise, causing vasoconstriction in its own right and stimulating aldosterone production via the vasopressin 1b receptor. Low-grade renal injury and autoimmune-mediated inflammation occur. High-salt diets can amplify this process by raising osmolality and triggering more fructose production. Thus, primary hypertension may result from the overactivation of a survival response triggered by fructose metabolism. Restricting salt and sugar and hydrating with ample water may be helpful in the prevention of primary hypertension. [ABSTRACT FROM AUTHOR]

We present the hypothesis that most cases of essential hypertension occur via two phases. The first phase is initiated by episodes of renal vasoconstriction induced by a hyperactive sympathetic nervous system, activation of the renin-angiotensin system, or hyperuricemia resulting from diet or genetics. During this phase the hypertension is salt resistant and renin dependent, and the kidney normal. Over time, preglomerular vascular disease develops (arteriolosclerosis), associated with tubulointerstitial inflammation; this shifts the hypertension to a salt-sensitive, volume-dependent, and renal-dependent pathway. This pathway unites many of the previous hypotheses on the etiology of hypertension, and offers insights into ways to prevent, ameliorate, or cure the underlying process. [Copyright &y& Elsevier]

Recent studies in both humans and experimental animals have led to renewed interest in uric acid and its association with hypertension, cardiovascular events and renal disease progression. This has also refuelled a longstanding debate regarding the precise role of this ubiquitous breakdown product of purine metabolism in these disease processes. Various lines of evidence suggest that uric acid may have a direct role in the pathogenesis of hypertension and vascular disease. Regardless of this possibility, it is apparent that serum uric acid levels serve as a powerful‘biomarker’ or independent predictor of prognosis and outcome in certain renal, cardiovascular and cerebrovascular diseases. Whether these outcomes can be improved by specifically treating asymptomatic hyperuricaemia remains inadequately resolved at this stage. Data from various animal studies suggests that lowering uric acid levels may be of benefit, but the crucial human studies are still lacking. This review will examine some of the recent evidence supporting a causal and contributory role for uric acid in cardiovascular and renal disease. How clarification of the role of uric acid may guide future treatment strategies will also be discussed. [ABSTRACT FROM AUTHOR]

The authors reply to letters written in response to the article "Effect of Allopurinol on Blood Pressure of Adolescents With Newly Diagnosed Essential Hypertension: A Randomized Trial."

Background The association between hyperuricemia and hypertension is controversial. Animal models, epidemiological data, and small clinical trials have favored a causative role for hyperuricemia in hypertension but more studies are necessary to elucidate putative mechanisms, population susceptibility, and potential for urate-lowering therapies (ULT) to decrease blood pressure (BP). Purpose To describe the background and design of the Serum Urate Reduction to Prevent Hypertension (SURPHER) study. Methods SURPHER is a single center, double-blinded, crossover trial in which participants are randomly assigned to allopurinol (300 mg) or placebo. Enrollment focused on adults 18–40 years old with baseline systolic blood pressure ≥ 120 and < 160 mm Hg or diastolic blood pressure ≥ 80 and < 100 mm Hg, and serum urate ≥ 5.0 mg/dL or ≥ 4.0 mg/dL for men or women, respectively. SURPHER recruitment targets participants without chronic kidney disease (estimated glomerular filtration rate > 60 mL/min/1.73 m2), and without prior diagnosis of gout or use of ULT to treat gout. The primary outcome is change from baseline in blood pressure assessed by 24 hour ambulatory blood pressure monitoring and mechanistic outcomes include changes in endothelial function as measured by flow-mediated dilation, as well as C-reactive protein levels. Results Since June 16, 2014 until present, SURPHER is recruiting participants in the city of Birmingham, Alabama. Limitations The study aims to enroll otherwise healthy young adults for a pharmacological intervention study with multiple study-related procedures. Challenges related to recruitment are anticipated and multiple strategies for increasing recruitment and retention are planned if necessary. [ABSTRACT FROM AUTHOR]

Argininosuccinate lyase (ASL) is required for the synthesis and channeling of L-arginine to nitric oxide synthase (NOS) for nitric oxide (NO) production. Congenital ASL deficiency causes argininosuccinic aciduria (ASA), the second most common urea-cycle disorder, and leads to deficiency of both ureagenesis and NO production. Subjects with ASA have been reported to develop long-term complications such as hypertension and neurocognitive deficits despite early initiation of therapy and the absence of documented hyperammonemia. In order to distinguish the relative contributions of the hepatic urea-cycle defect from those of the NO deficiency to the phenotype, we performed liver-directed gene therapy in a mouse model of ASA. Whereas the gene therapy corrected the ureagenesis defect, the systemic hypertension in mice could be corrected by treatment with an exogenous NO source. In an ASA subject with severe hypertension refractory to antihypertensive medications, monotherapy with NO supplements resulted in the long-term control of hypertension and a decrease in cardiac hypertrophy. In addition, the NO therapy was associated with an improvement in some neuropsychological parameters pertaining to verbal memory and nonverbal problem solving. Our data show that ASA, in addition to being a classical urea-cycle disorder, is also a model of congenital human NO deficiency and that ASA subjects could potentially benefit from NO supplementation. Hence, NO supplementation should be investigated for the long-term treatment of this condition. [Copyright &y& Elsevier]